Researchers have long pointed out the fact that H. polygyrus, a nematode parasite, must produce a protein that effectively down regulates and suppresses the host's ability to mount an inflammatory response. It has also been known that nematode fatty acid and retinol-binding (FAR) proteins that are entirely alpha-helical in structure have been shown to bind fatty acids. FAR proteins have been shown to bind inflammatory mediators and their precursors. Inflammatory mediators act as signals to recruit or activate other cells. The role of inflammatory mediators is to alert host body cells to infection and to recruit them to mount an inflammatory response to help clear the infection. If a FAR protein is intercepting these mediators, the mediator signals never reach the cells that are being recruited. Therefore, the inflammatory response directed at clearing the parasitic infection is ablated. It is postulated that a FAR protein binding these inflammatory mediators would explain how H. polygyrus is able to survive in the host's intestines without being expelled (even in mice that have been repeatedly immunized or infected) and how chronic infections are formed and maintained without any significant damage to the larvae.
For decades, the literature regarding H. polygyrus has described an elusive immunomodulatory factor (IMF) that downregulates the host immune response. It is known that immunosuppression is present across both classes of nematodes. It has also been known that nematodes are able to cause these chronic infections but the means by which chronic infections are achieved remains controversial. For years, hypotheses have been proposed as to how intestinal helminths (parasitic nematodes) have been able to evade the host immune system. The main focus of research has been directed to immunomodulation, or down regulation of the host's immune system (immunosuppression), but to date progress has been slow.
To date, to the best knowledge of the inventor, no research group has been able to isolate or identify the unknown immunomodulatory protein from H. polygyrus. Researchers have postulated that any immunomodulatory proteins acting on the host's immune system are most likely released from the parasite as E/S proteins, that is, excretion proteins presently being excreted as useless or harmful to the nematode or secretion proteins present as a product or a release from the nematode to perform a function useful to the nematode.
Researchers have described the immunosuppression that is occurring in the presence of nematodes by demonstrating that many nematodes reside in tissue sites in a host surrounded by inflammatory cells but apparently unaffected by the presence of the inflammatory cells. For example, in one report, “in H. polygyrus, the L3 and L4 larvae develop in the muscularis externa of the mouse intestine for a period of 8-9 days before returning to the gut lumen as adults, in immune challenged mice, these sites of development become surrounded by inflammatory cells and despite the intensity of local cellular activity, few if any worms are actually killed within such foci of cellular activity. There is a very obvious stunting of worms and their capacity to survive in the gut lumen is greatly impaired once they have completed development. However, larvae can survive in such gramlomata for weeks and still succeed in returning to the gut lumen.” Jerzy M. Behnke, Christopher J. Barnard, and Derek Wakelin. “Understanding Chronic Nematode Infections: Evolutionary Considerations, Current Hypotheses and the Way Forward.” International Journal for Parasitology (Vol. 22, No. 7, 1992): 861-907.
Very little is known about nematode FAR proteins. What is known is that they appear to bind retinol (a vitamin A derivative) and certain fatty acids (most interestingly, inflammatory mediators and their precursors). The importance of these particular ligands, and the immunological aspects of H. polygyrus infection, make for a very interesting combination.
The Connection Between Retinol Binding and Immunity:
Firstly, it has been shown in order for a host to successfully ‘clear’ or ‘rid itself’ of an H. polygyrus infection, it must produce what is known as a Th-2 type immune response. This type of immune response, known as a humoral response (involving antibodies), is usually directed at extracellular organisms (those originating from outside the host's body). However, poor-responding mice have little or no ability to decrease worm burden or fight infection to H. polygyrus and mount a Th-1 type response instead. This type of immunity is referred to as cell-mediated immunity, and is usually reserved for fighting intracellular parasites (originating from inside a host cell; e.g. viruses or tumors). This Th-1 type response is ineffective at protecting the host from infection and thus the infection becomes chronic. It has been proposed the H. polygyrus produces an E/S protein which is able to ‘switch’ the Th-type of the response, or trick the host into producing a Th-1 type response which is not beneficial and allows the parasite to maintain the chronic infection. The link between retinol and a retinol binding protein (like a FAR protein) is able to explain this phenomenon. When a retinol binding protein binds retinol it sequesters the retinol, making it unavailable to the host. It has been shown retinol is in fact a costimulator of CD4+ T cells (the type of cell that determines the Th type of the response) and the CD4+ T cells cannot mount a functional Th-2 type response without retinol. This would effectively ‘switch’ the Th-type to a type 1. This, therefore, would explain the Th-type switching that we see during H. polygyrus infections and the subsequent chronicity of infection.
The Connection Between Fatty Acid Binding and Immunity:
Nematode FAR proteins have been shown to bind fatty acids that fall into the categories of inflammatory mediators and their precursors. Inflammatory mediators are signals released by cells that recruit or activate other cells. Their role is to alert other cells to infection and recruit them to mount an inflammatory response to help clear the infection. If a FAR protein is intercepting these mediators, the mediators never reach the cells being recruited and therefore the inflammatory response that should be directed at clearing the parasitic infection is ablated. Researchers have long pointed out the fact H. polygyrus must produce a protein that effectively downregulates and suppresses the host's ability to mount an inflammatory response. Unfortunately, no one has been able to produce a mechanism or identify a particular protein responsible (until now). A FAR protein binding these inflammatory mediators explains how H. polygyrus is able to survive in the host's intestines without being expelled (even in mice repeatedly immunized or infected) and how chronic infections are formed and maintained without any significant damage to the larvae (a phenomenon well documented, but still unexplained).
For decades now the literature regarding H. polygyrus has described an “elusive” immunomodulatory factor (IMF) that downregulates the host immune response. It is known that this immuno-depression is easily demonstrable across both classes of Nematoda. The potential chronicity of nematode infections is not disputed, but the means through which chronic infections are achieved has not been determined.
Researchers have agreed any immunomodulatory proteins in existence would be most likely found within the E/S proteins. However, researchers have had no idea of the relevant factors needed to be identified to identify or isolate the immunomodulatory protein that downregulates the host's immune response.
Many of these studies directed to immunomodulatory proteins have turned to H. polygyrus as the primary model, for a number of reasons: 1) it is an excellent lab model; 2) it establishes chronic infections in many mouse strains; 3) there is a long history of research on this organism, as it was originally proposed as a model for human hookworm decades ago.
The majority of research performed on H. polygyrus has focused on the immunosuppression occurring. The downregulation described by many researchers fits into what would be expected by a FAR protein, that is, many nematodes seem to reside in tissue sites surrounded by inflammatory cells but apparently unaffected by their presence. This must be caused by localized suppression of the immune response and the cause of the suppression must be an E/S protein. An E/S protein is directed into the site of downregulated immunity because it is produced at the exact time during infection and is an E/S protein.
In the H. polygyrus, the L3 and L4 larvae develop in the muscularis externa of the mouse intestine for a period of 8-9 days before returning to the gut lumen of adults. In immune challenged mice, these sites of development become surrounded by inflammatory cells and despite the intensity of local cellular activity, few if any worms are actually killed within such foci of cellular activity. There is a very obvious stunting of worms and their capacity to survive in the gut lumen is greatly impaired once they completed development. However, larvae can survive such gramulomata for weeks and still succeed in returning to the gut lumen. Jerzy M. Behnke, Christopher J. Barnard, and Derek Wakelin. “Understanding Chronic Nematode Infections: Evolutionary Considerations, Current Hypotheses and the Way Forward.” International Journal for Parasitology (Vol. 22, No. 7, 1992): 861-907.
H. polygyrus has been used as a model to demonstrate chronic infections caused by helminths. If this model does represent helminth infections in general, it may be possible to target more than just the nematodes closely related to H. Polygyrus, such as the Trichostrongylus species or the Ancylostoma hookworm which infects millions of individuals.
Because a FAR protein has to actually bind to its ligand to cause immunosuppression, the ligand therefore is a complexing agent with coordination bonding by means of a coordinating atom with electron pairs to donate or share, a procedure to inhibit the formulation of the chronic infection is to physically block the protein from binding its ligands. Two main methods may be used:                1) Antibody recognition of Hp20 protein. Antibodies produced by the host during an H. polygyrus infection can bird to both the native form and the recombinant form of Hp20 protein. The fact that the Hp20 protein is highly immunogenic causes it to be a target for antibody-mediated immunity. The treatment would involve the actual administration of antibodies during infection, or prophylactic treatment by immunization using the isolated Hp20 protein.        2) Drug-mediated targeting of Hp20 protein. A drug or protein designed to specifically block the active binding site of the Hp20 protein would prevent ligand binding.        
The above description of the presence of nematodes in a host body and concomitant chronic infection has been known but the key as to how the parasite was managing to suppress the host immunity has not been known.
It is an object of the present invention to provide a key as to how the H. polygyrus manages to suppress the host immunity.
It is an object of the present invention to provide a method to target helminth infections of hosts in general.
It is an object of this invention to provide a method to target infections, chronic and acute, of nematodes closely related to H. polygyrus such as nematodes of the species Trichostrongylus or the Ancylostoma species, as well as other helminth infections.
It is an object of this invention to provide a method to target infections, chronic and acute, of nematodes, specifically H. polygyrus. 
It is an object of this invention to define, identify and isolate protein complexes having immunosuppressive activity of a host's ability to mount an inflammatory response to the presence of a helminth.
It is an object of this invention to provide compositions of protein molecules having immunosuppressive activity, methods and procedures for identification, preparation, separation and analysis of such protein molecules.
It is an object of this invention to define, identify and isolate a protein molecule comprising a FAR-1 protein from H. polygyrus having immunosuppressive activity from a parasite.